Five viral agents associated with the bovine respiratory disease (BRD) complex—Bovine Herpes Virus Type-1 (BHV-1), also known as infectious bovine rhinotracheitis virus (IBR), Bovine viral diarrhea virus (BVDV) Types 1 and 2, Bovine Respiratory Syncytial Virus (BRSV), and Parainfluenza Virus (PI3), cause respiratory and reproductive system infections of great economic importance to the cow-calf and dairy industries worldwide. BRD causes a broad array of clinical syndromes including acute onset respiratory disease and abortion. The respiratory form of BRD is characterized by inflammation, swelling, hemorrhage, and necrosis of the mucous membranes of the respiratory tract and may be accompanied by high fever, anorexia, depression, nasal discharge, labored breathing, and inflamed muzzle. Abortions induced by IBR and BVDV virus can occur in all three trimesters, but chiefly during the last half of gestation, and often without evidence of other clinical signs (Ellis et al. (1996) JAVMA 208:393-400; Ellsworth et al. (1994) In: Proceedings, 74th Conference of Research Workers in Animal Disease:34).
Bovine Herpes Virus Type-1 (BHV-1), is a member of the alphaherpesviridae subfamily, and produces a variety of clinical forms of disease in cattle, including respiratory and genital infections, conjunctivitis, encephalitis, and abortions. Previous attempts at controlling BHV-1 infection have utilized vaccines comprising live attenuated virus (Gerber, J. D., et al., 1978, Am. J. Vet. Res. 39:753-760; Mitchell, D., 1974, Can. Vet. Jour. 15:148-151), inactivated virus (Frerichs, G. N., et al., 1982, Vet. Rec. 111:116-122), and viral subunits such as, e.g., one of the three major BHV-1 glycoproteins, which have been designated in the art as gI, gIII, and gIV (Babiuk, L. A., et al., 1987, Virology 159:57-66; van Drunen, S., et al., 1993, Vaccine 11:25-35). In addition, the ability of a recombinant, truncated version of the BHV-1 gIV glycoprotein (designated in the art as BHV-1 tgIV) to induce mucosal immunity against BHV-1 has been demonstrated (van Drunen, S., et al., 1994, Vaccine, 12:1295-1302). However, the art-recognized BHV-1 vaccines are contraindicated for use in pregnant cattle, seropositive or seronegative, and also contraindicated for use in calves nursing pregnant cows.
BVDV Types 1 and 2 have been implicated in a variety of clinical syndromes. Studies have established that the virus causes severe primary respiratory disease; that persistently infected (PI) cattle are a major source of infection for susceptible calves; and that BVDV infects white cell reservoirs, causing profound and broad-based deficits in the immune system. Ellis et al. (1996) JAVMA 208:393-400; Baum et al. (1993) The Compendium Collection: Infectious Disease in Food Animal Practice. Trenton, N.J. Veterinary Learning Systems-113-121; Meyling et al. (1987) Agric Pestivirus Infect Rumin 225-231. Abortion or mummification can result when pregnant cattle become infected especially during the first trimester. Bolin et al. (1989) Am J. Vet Res 52:1033-1037. Mucosal disease, another often fatal manifestation of bovine viral diarrhea (BVD), results from early fetal infection with a noncytopathic BVDV biotype, development of immunotolerance to the virus, birth of a persistently infected (PI) calf, and subsequent superinfection with a cytopathic BVDV biotype. Bolin et al. (1989) Am J. Vet Res 52:1033-1037. BVDV Type 2, once recognized chiefly as a hemorrhagic BVDV isolate mostly in dairy herds, has become the predominant strain isolated in most regions of the United States from both BVD-related abortions and respiratory cases. Van Oirschot et al. (1999) Vet Micro 64:169-183.
BVDV is classified in the pestivirus genus and Flaviviridae family. It is closely related to viruses causing border disease in sheep and classical swine fever. Infected cattle exhibit “mucosal disease” which is characterized by elevated temperature, diarrhea, coughing and ulcerations of the alimentary mucosa (Olafson, et al., Cornell Vet. 36:205-213 (1946); Ramsey, et al., North Am. Vet. 34:629-633 (1953)). The BVD virus is capable of crossing the placenta of pregnant cattle and may result in the birth of PI calves (Malmquist, J. Am. Vet. Med. Assoc. 152:763-768 (1968); Ross, et al., J. Am. Vet. Med. Assoc. 188:618-619 (1986)). These calves are immunotolerant to the virus and persistently viremic for the rest of their lives. They provide a source for outbreaks of mucosal disease (Liess, et al., Dtsch. Tieraerztl. Wschr. 81:481-487 (1974) and are highly predisposed to infection with microorganisms causing diseases such as pneumonia or enteric disease (Barber, et al., Vet. Rec. 117:459-464 (1985).
According to BVDV virus growth studies in cultured cells, two viral biotypes have been classified: viruses that induce a cytopathic effect (cp) and viruses that do not induce a cytopathic effect (ncp) in infected cells (Lee et al., Am. J. Vet. Res. 18: 952-953; Gillespie et al., Cornell Vet. 50: 73-79, 1960). Cp variants can arise from the PI animals preinfected with ncp viruses (Howard et al., Vet. Microbiol. 13: 361-369, 1987; Corapi et al., J. Virol. 62: 2823-2827, 1988). Based on the genetic diversity of the 5′ non-translated-region (NTR) and the antigenic differences in the virion surface glycoprotein E2 of BVD viruses, two major genotypes have been proposed: type I and II. BVDV type 1 represents classical or traditional virus strains which usually produce only mild diarrhea in immunocompetent animals, whereas BVDV type 2 are emerging viruses with high virulence which can produce thrombocytopenia, hemorrhages and acute fatal disease (Corapi et al., J. Virol. 63: 3934-3943; Bolin et al., Am. J. Vet. Res. 53: 2157-2163; Pellerin et al., Virology 203: 260-268, 1994; Ridpath et al., Virology 205: 66-74, 1994; Carman et al., J. Vet. Diagn. Invest. 10: 27-35, 1998). Type I and II BVDV viruses have distinct antigenicity determined by a panel of monoclonal antibodies (Mabs) and by cross-neutralization using virus-specific antisera raised in animals (Corapi et al., Am. J. Vet. Res. 51: 1388-1394, 1990). Viruses of either genotype may exist as one of the two biotypes, cp or ncp virus.
Studies from BVD virus infected animals suggest that BVD viruses induce both B-cell and T-cell responses in animals (Donis et al., Virology 158: 168-173, 1987; Larsson et al., Vet. Microbiol. 31: 317-325, 1992; Howard et al., Vet. Immunol. Immunopathol. 32: 303-314, 1992; Lambot et al., J. Gen. Virol. 78: 1041-1047, 1997; Beer et al., Vet. Microbiology. 58: 9-22, 1997).
A number of BVDV vaccines have been developed using chemically inactivated BVD viral isolates (Fernelius et al., Am. J. Vet. Res. 33: 1421-1431, 1972; Kolar et al., Am. J. Vet. Res. 33: 1415-1420, 1972; McClurkin et al., Arch. Virol. 58: 119, 1978). Multiple doses are required for the inactivated viral vaccines to achieve primary immunization. Some inactivated BVDV vaccines provide protection against infection by type I BVDV only (Beer et al., Vet. Microbiology. 77:195-208, 2000). Fetal protection has not been achieved with inactivated BVDV vaccines due to a short duration of immunity and an inefficient cross-type protection (Bolin, Vet. Clin. North Am. Food Anim. Pract. 11: 615-625, 1995).
Modified-live virus (MLV) vaccines, on the other hand, offer a higher level of protection. Currently, licensed BVDV MLV vaccines are produced using attenuated viruses obtained via repeated passage in bovine or porcine cells (Coggins et al., Cornell Vet. 51: 539-, 1961; Phillips et al., Am. J. Vet. Res. 36: 135-, 1975), or using chemically modifiedviruses which exhibit a temperature-sensitive phenotype (Lobmann et al., Am. J. Vet. Res. 45: 2498-, 1984; 47: 557-561, 1986). A single dose of MLV vaccine is sufficient for immunization, and duration of the immunity can last for years in vaccinated cattle. However, as these vaccines have been developed using type I BVDV virus strains, the protection is against type I virus only. Moreover, the available BVDV vaccines are not indicated for use in pregnant cattle or calves nursing pregnant cows.
PI3 virus typically produces only mild disease when acting alone; however, the virus predisposes the respiratory tract to secondary infection with more pathogenic organisms including IBR virus, BRSV, and BVDV, resulting in the classic shipping fever syndrome. Of the various viruses known to cause respiratory disease in cattle, PI3 virus is the most widespread. Ellis et al. (1996) JAVMA 208:393-400.
BRSV has a preference for the lower respiratory tract, and severity of infection is determined chiefly by the immune system's response to key viral proteins. Bolin et al. (1990) Am J Vet Res 51:703. Affected cattle generally show nonspecific signs including serous nasal and ocular discharge, a mild, often biphasic fever, and dry, hacking cough. More severely affected cattle develop a harsh cough, show labored, open-mouth breathing, and frothy saliva around the mouth, and may quit eating and drinking. Ellis et al. (1996) JAVMA 208:393-400.
Leptospirosis, caused by spirochetes of the genus Leptospira, is an economically important zoonotic infection of livestock. Leptospira borgpetersenii serovar hardjo (L. hardjo) and L. interrogans serovar pomona (L. pomona) are the two serovars most commonly associated with cattle leptosporosis worldwide. In one survey of US cattle, 29% reacted serologically with L. hardjo, and 23% with L. pomona. Leptospires invade the body via mucous membranes or broken skin, and are disseminated via the blood. They display tropisms for the kidney and genital tract, and less commonly the vitreous humor of the eye and the central nervous system. The most common means of infection is by direct or indirect contact with infected urine, milk, or placental fluids, but venereal and trans-ovarian transmission are also known. Leptospiral infection of cattle may result in acute fever, agalactia, abortion, or birth of premature and weak infected calves, and may contribute to breeding failures and low conception rates. Infections can be treated with antibiotics, but they may be inapparent in cattle that are not lactating or pregnant. In such cattle they establish acute or chronic infection of the kidneys, resulting in urinary shedding of virulent organisms which in turn may infect other animals or their human handlers. Immunity to Leptospira is serovar specific, and although vaccines have been available for many years, most induce only a poor and short-lived immunity.
There is therefore a need for development of combination vaccines that provide protection against a large variety of antigens that are safe for pregnant and nursing cows and their offspring and meet dairy and beef cow market needs. The present invention provides vaccines for the treatment and prevention of the major infectious causes of respiratory and reproductive disease in animals, such as cows and calves. The present invention further provides immunogenic compositions and methods of treating or preventing diseases or disorders in animals.